JP7340542B2 - 1-imidazothiadiazolo-2H-pyrrol-5-one derivative - Google Patents

Description

The present invention relates to 1-imidazothiadiazolo-2H-pyrrol-5-one derivatives, processes for their preparation, pharmaceutical compositions containing them, and their use as medicaments.

It has been reported in the literature (Kaminski et al. in Neuropharmacology, 54, (2008) 715) (Loscher et al. in CNS drugs, October 2016).

Several SV2A ligands have been described in the prior art, including those described below in our co-pending patent applications.

WO 2011/047860 discloses 2-oxo-1-pyrrolidinylimidazothiadiazole derivative compounds of the following formula A:

During the ceremony,
R ¹ is C _1-4 alkyl containing at least one halogen substituent;
R ² is either halogen or C _1-4 alkyl containing at least one halogen substituent;
R ³ is C _1-4 alkyl containing at least one hydroxy or alkoxy substituent.

WO 2008/132139 discloses antiepileptic compounds of formula (B):

During the ceremony,
Y is O or S;
R ¹ is hydrogen or C _1-6 alkyl,
R ² is hydrogen;
R ³ is -CONR ⁵ R ⁶ , -COR ⁷ , imidazolyl, imidazopyridinyl, imidazopyridazinyl,
R ⁵ , R ⁶ are the same or different and independently selected from hydrogen and C _1-6 alkyl;
R ⁷ is C _1-6 alkyl;
Z is imidazolidin-1-yl, 1,3-oxazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,3-thiazol-3(2H)-yl, 1,3 -thiazolidin-3-yl, piperidin-1-yl, azepan-1-yl, 5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl, hexahydro-4H-thieno[3,2 -b]pyrrol-4-yl, 2,3-dihydro-1H-thieno[3,4-b]pyrrol-1-yl, 1,3-benzothiazol-3(2H)-yl, 1,3-benzo Oxazol-3(2H)-yl, pyrazolo[1,5-a]pyridin-1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 3,4-dihydroquinolin-1(2H )-yl, 1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl, 1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl It is a monocyclic or bicyclic heterocyclic moiety.

In certain embodiments of WO 2008/132139, the Z=Y portion of formula (B) can be:

The above compounds have been described for use as drugs for the treatment of epilepsy, epileptic seizures, seizure disorders, convulsions, especially refractory seizures.

Despite the availability of antiepileptic drugs, there remains a persistent problem in seizure control that occurs in patients who do not respond at all or respond poorly to currently available treatments.

These patients are thought to be resistant to treatment and pose a major challenge to the medical community. It is estimated that approximately 30% of epilepsy patients are classified as refractory. Therefore, there is a need to develop new drugs that specifically target this patient population.

Additionally, a problem that can be encountered in developing compounds for therapeutic use is the ability of certain compounds to induce CYP450 enzymes. Induction of such enzymes could affect patient exposure of such compounds, or other compounds that may be co-administered therewith, thereby potentially altering their respective safety or efficacy. There is a possibility that It is therefore desirable to develop compounds that also minimize the possibility of such induction.

The present invention relates to 1-imidazothiadiazolo-2H-pyrrol-5-one derivatives having formula (I), their geometric isomers, enantiomers, diastereoisomers, isotopes and mixtures, or their pharmaceutical Provide acceptable salt:

Further aspects of the invention will become apparent from the detailed description.

The present invention relates to 1-imidazothiadiazolo-2H-pyrrol-5-one derivatives according to formula (I):

During the ceremony,
R ¹ is C _1-4 alkyl or C _3-5 cycloalkyl, any of these groups optionally substituted by one or more halogen substituents;
R ² is C _1-4 alkyl substituted with one hydroxy or alkoxy substituent;
R ³ is halogen; C _1-4 alkyl or C _3-4 cycloalkyl, any of these groups optionally substituted by one or more halogen atoms.

Tautomers, geometric isomers, enantiomers, diastereomers, isotopes and mixtures or pharmaceutically acceptable salts of the compounds of formula (I), as well as any deuterated variants, are also contemplated by the present invention. Included within the scope of.

The compounds according to formula (I) therefore differ from the compounds disclosed in the prior art.

In one embodiment, R ¹ is C _1-4 alkyl optionally substituted with one or more halogen substituents. In a first aspect of this embodiment, R ¹ is unsubstituted C _1-4 alkyl. In a second aspect of this embodiment, R ¹ is C _1-4 alkyl substituted with one or more halogens. Preferably, in this particular embodiment, the halogen substituent is a chloro or fluoro substituent.

In another embodiment, R ¹ is C _3-5 cycloalkyl optionally substituted with one or more halogen substituents. In a first aspect of this embodiment, R ¹ is unsubstituted C _3-5 cycloalkyl. In a second aspect of this embodiment, R ¹ is C _3-5 cycloalkyl substituted with one or more halogens. Preferably, in this particular embodiment, the halogen substituent is a fluoro substituent.

In certain embodiments, R ¹ is C _1-4 alkyl substituted with one or more halogen substituents. In certain aspects of this particular embodiment, R ¹ is C _1-4 alkyl substituted with one or more fluoro substituents.

Suitable examples of R ¹ groups include n-propyl, 2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3 , 3,3-trifluoropropyl, 2-fluoroethyl and 2,2-difluorocyclopropyl.

Particular examples of ^R groups include n-propyl, 2-chloro-2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoropropyl, Ethyl and 2,2-difluorocyclopropyl are mentioned. In a preferred embodiment, R ¹ is 3,3,3-trifluoropropyl or 2,2-difluorocyclopropyl.

In one embodiment, R ² is C _1-4 alkyl substituted with one hydroxy. In another embodiment, R ² is C _1-4 alkyl substituted with one alkoxy substituent. In certain aspects of this embodiment, R ² is C _1-4 alkyl substituted with a methoxy substituent.

In certain embodiments, R ² is hydroxymethyl or methoxymethyl.

In a preferred embodiment, R ² is methoxymethyl.

In a first embodiment, R ³ is C _1-4 alkyl optionally substituted by one or more halogen atoms. In a first aspect of this embodiment, R ³ is unsubstituted C _1-4 alkyl. In a second aspect of this embodiment, R ³ is C _1-4 alkyl substituted with one or more halogen atoms. Suitably, in this particular aspect, R ³ is C _1-4 alkyl substituted with one or more fluoro atoms.

In a second embodiment, R ³ is C _3-4 cycloalkyl optionally substituted by one or more halogen atoms. In a first aspect of this embodiment, R ³ is unsubstituted C _3-4 cycloalkyl. In a second aspect of this embodiment, R ³ is C _3-4 cycloalkyl substituted with one or more halogen atoms. Suitably, in this particular aspect, R ³ is C _3-4 cycloalkyl substituted with one or more fluoro atoms.

In a third embodiment, ^R3 is halogen. In certain aspects of this embodiment, R ³ is chloro.

Suitable examples of R ³ include methyl, difluoromethyl, chloro, trifluoromethyl and 1-fluorocyclopropyl.

In a preferred embodiment, R ³ is methyl or difluoromethyl.

All combinations of the above embodiments and examples of R ¹ , R ² and R ³ groups are included within the scope of the invention.

In a more particular embodiment, the compound of formula (I) is:
- R ¹ is C _1-4 alkyl or C _3-5 cycloalkyl, any of these groups optionally substituted by one or more halogen substituents;
・R ² is C _1-4 alkyl substituted with an alkoxy substituent,
-R ³ is C _1-4 alkyl substituted with one or more halogen atoms.

Particular compounds according to the invention are those selected from the group consisting of:
1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole- 5-on;
1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2 -trifluoroethyl)-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3 -trifluoropropyl)-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one ;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoroethyl )-2H-pyrrol-5-one;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoropropyl )-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole-5 -on;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- trifluoroethyl)-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoro ethyl)-2H-pyrrole-;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- trifluoroethyl)-2H-pyrrol-5-one;
1-[[6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2 ,2-trifluoroethyl)-2H-pyrrol-5-one;
3-(2-chloro-2,2-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole -5-yl]methyl]-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro propyl)-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- trifluoropropyl)-2H-pyrrol-5-one;
3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl] methyl]-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2-difluoropropyl )-2H-pyrrol-5-one;
3R-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl ]Methyl]-2H-pyrrol-5-one;
3S-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl ]Methyl]-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3R-[2,2-difluorocyclopropyl] -2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3S-[2,2-difluorocyclopropyl] -2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3R-[2,2-difluorocyclo propyl]-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3S-[2,2-difluorocyclo propyl]-2H-pyrrol-5-one;
3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]- 2H-pyrrol-5-one;
1-[[2-(hydroxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro propyl)-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- trifluoropropyl)-2H-pyrrol-5-one; and 1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5- yl]methyl]-3-(2,2,2-trifluoroethyl)-2H-pyrrol-5-one.

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and apply uniformly throughout the specification and claims, unless other clearly indicated definitions provide a broader definition. intended to be done.

"C _1-4 alkyl" refers to an alkyl group having 1 to 4 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like. A "C _1-4 alkyl" group may be substituted with one or more substituents selected from halogen, hydroxy or alkoxy.

The term "C _3-5 cycloalkyl" as used herein refers to a monovalent group of 3 to 5 carbon atoms derived from a saturated monocyclic hydrocarbon. Exemplary C _3-5 cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Examples of C _3-5 cycloalkyl groups include C _3-4 cycloalkyl, which refers to groups having 3 to 4 carbon _atoms . Exemplary C _3-4 cycloalkyl groups are cyclopropyl and cyclobutyl.

Any moiety "H" in formula (I) may be the isotope hydrogen, deuterium or tritium.

"Hydroxy" represents a group of the formula -OH.

"Alkoxy" refers to the group -OR, where R includes "C _1-4 alkyl".

"Halogen" refers to fluoro, chloro, bromo and iodo atoms, preferably fluoro and chloro.

"Pharmaceutically acceptable salts" according to the present invention include the therapeutically active non-toxic acid or base salt forms that the compounds of formula (I) are capable of forming.

Acid addition salt forms of compounds of formula (I) which occur in their free form as bases may be prepared using suitable acids such as inorganic acids such as hydrogen halides, such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid. or, for example, acetic acid, trifluoroacetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid , benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. by treatment of the free base.

Compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base addition salt forms, such as metal or amine salts, by treatment with suitable organic and inorganic bases. . Suitable base salt forms include, for example, ammonium salts, alkali salts and alkaline earth metal salts, for example lithium, sodium, potassium, magnesium, calcium salts, salts with organic bases, for example N- Included are methyl-D-glucamine, hydrabamine salts, as well as salts with amino acids, such as arginine, lysine, and the like.

Conversely, the salt forms can be converted to the free form by treatment with a suitable base or acid.

The compounds of formula (I) and their salts may be in the form of solvates included within the scope of the invention. Such solvates include, for example, hydrates, alcoholates, and the like.

The compounds of formula (I) and/or their intermediates may have at least one asymmetric center in their structure. This asymmetric center may exist in the R or S configuration, and the above R and S notations are used in Pure Appl. Chem. , 45 (1976) 11-30. The invention therefore also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms, of the compounds of formula (I) or mixtures thereof, including all possible mixtures of stereoisomers. In the context of the present invention, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned. . The expression "enantiomerically pure" as used herein refers to a compound having an enantiomeric excess (ee) of greater than 95%.

Compounds according to the invention may exist in various polymorphic forms. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of this invention.

Compounds of formula (I) according to the invention can be prepared analogously to conventional methods, as understood by those skilled in the art of synthetic organic chemistry.

According to one embodiment, compounds having general formula (I) in which R ² is C _1-4 alkyl substituted by one alkoxy substituent are prepared using an amine of formula (II) according to the following formula: , can be prepared by reductive amination of a hydroxylactone of formula (III):

wherein R ¹ and R ³ have the same definitions as defined above for compounds of formula (I).

This reaction may be carried out according to the procedures described in the patent applications WO 01/62726, WO 2006/128792 and WO 2008/132139.

Compounds of formula (III) may be prepared according to the methods described in the patent applications WO 01/62726 or WO 2006/128792 or according to any method known to the person skilled in the art.

Compounds of formula (II) in which R ² is C _1-4 alkyl substituted with one alkoxy substituent may be prepared by reducing compounds of formula (IV) according to the following formula:

wherein R ³ has the same definition as defined above for compounds of formula (I).

This reaction may be carried out using a reducing agent such as triphenylphosphine in a THF/water mixture at room temperature or according to any method known to those skilled in the art.

Compounds of formula (IV) in which R ² is C _1-4 alkyl substituted with one alkoxy substituent may be prepared by transforming compounds of formula (V) according to the following formula:

where R ³ has the same definition as defined above for compounds of formula I.

This reaction is carried out using a sulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as N,N-diisopropylethylamine in dichloromethane at 0°C or according to any other method known to those skilled in the art. ) followed by treatment of the intermediate with an azide derivative such as sodium azide in DMF at 0°C.

Alternatively, compound (II) can be prepared using a sulfonyl chloride such as methanesulfonyl chloride at 0° C. in the presence of a base such as N,N-diisopropylethylamine in dichloromethane or a chlorinating agent such as thionyl chloride, or as described in the art. 3 by treating compound (V) according to any other method known in the art, followed by treatment of the intermediate with hexamethylenetetramine, followed by acid hydrolysis of the quaternary ammonium salt of the intermediate. It may also be prepared in a step series.

Compounds of formula (V) in which R ² is C _1-4 alkyl substituted with one alkoxy substituent may be prepared by hydroxymethylation of compounds of formula (VI) according to the following formula:

wherein R ³ has the same definition as defined above for compounds of formula (I).

This reaction may be carried out in a polar solvent such as dioxane at 100° C. under acidic conditions using a formylating agent such as paraformaldehyde, or according to any other method known to those skilled in the art.

Compounds of formula (VI) in which R ² is C _1-4 alkyl substituted by one alkoxy substituent can be prepared by reacting a compound of formula (VII) with a bromo derivative of formula (VIII) according to the following formula: It can be synthesized by:

where R ³ has the same definition as given above for compounds of formula (I).

This reaction may be carried out using procedures described in the literature or known to those skilled in the art.

Compounds of formula (VII) and formula (VIII) are commercially available or can be synthesized according to any method known to those skilled in the art.

According to another embodiment, the compounds of formula (I), wherein R ² is C _1-4 alkyl substituted by one alkoxy substituent, can be combined with compounds of formula (V) and formula (IX ) can be synthesized by reacting with pyrrolon:

wherein R ¹ and R ³ have the same definitions as defined above for compounds of formula (I).

This reaction may be carried out using an acid such as p-toluenesulfonic acid in an aprotic solvent such as sulfolane at elevated temperature.

Compounds of formula (IX) may be prepared by deprotecting compounds of formula (X) according to the following formula:

where R ¹ has the same definition as defined above for compounds of formula (I) and P is an optionally substituted protecting group such as a benzyl group.

This reaction may be performed according to any standard deprotection method known to those skilled in the art.

Compounds of formula (X) may be prepared by reductive amination of hydroxylactones of formula (III) with amines of formula (XI).

wherein R ¹ has the same definition as defined above for compounds of formula (I) and P is an optionally substituted protecting group such as a benzyl group.

This reaction may be carried out according to the procedures described in the patent applications WO 01/62726, WO 2006/128792 and WO 2008/132139.

According to another embodiment, the compounds of formula (I), wherein R ² is C _1-4 alkyl substituted by one alkoxy substituent, can be combined with compounds of formula (VI) and formula (XII ) can be synthesized by a Friedel-Crafts type reaction with pyrrolon:

wherein R ¹ and R ³ have the same definitions as defined above for compounds of formula (I).

This reaction involves the elimination of a chlorine atom or a p-toluenesulfonyl group, etc., in the presence of a Lewis acid such as zinc chloride or ferric chloride in a polar solvent such as sulfolane or dioxane at temperatures ranging from 100 to 120°C. It may be carried out using pyrrolones of formula (XII) with group (Y) or according to any procedure described in the literature or known to the person skilled in the art.

Compounds of formula (XII) are prepared from the corresponding pyrrolones of formula (IX) according to the methods described in PCT patent application WO 2006/128693 or according to any other method known to those skilled in the art. can be done.

Alternatively, compounds of formula (I) in which R ² is C _1-4 alkyl substituted by one alkoxy substituent may be synthesized by oxidizing compounds of formula (XIII) according to the following formula:

wherein R ¹ and R ³ have the same definitions as defined above for compounds of formula (I). This reaction can be carried out at room temperature using an oxidizing agent such as sodium periodate in a polar solvent such as methanol, or by any method known to those skilled in the art.

Compounds of formula (XIII) in which R ² is C _1-4 alkyl substituted by one alkoxy substituent can be prepared by reacting a compound of formula (V) with a pyrrolidone of formula (XIV) according to the following formula: Can be prepared by:

This reaction may be carried out using an acid such as p-toluenesulfonic acid in an aprotic solvent such as sulfolane at elevated temperature.

Pyrrolidones of formula (XIV), in which R ¹ has the same definition as defined above for compounds of formula (I), are of the formula ( XV) can be synthesized in a three-step sequence by deprotection of the pyrrolidone:

The protection-deprotection step may be performed by any method known to those skilled in the art. The selenylation reaction involves deprotonation using a strong base such as lithium bis(trimethylsilyl)amide or lithium diisopropylamide in a polar solvent such as tetrahydrofuran at a low temperature such as -78 °C, followed by phenylselenenyl chloride or bromide. This may be done by trapping the enolate by a selenylating agent such as.

Pyrrolidone (XVII) or (XVI) is prepared according to the method described in patent application WO 2006/128792 or WO 2011/047860 or according to any method known to the person skilled in the art. obtain.

Compounds of formula (I) in which R ² is C _1-4 alkyl substituted with one hydroxy substituent are compounds of formula (I) in which R ² is C _1-4 alkyl substituted with one alkoxy substituent. can be prepared by dealkylation of compounds of This reaction may be carried out at room temperature in a non-polar solvent such as dichloromethane using a dealkylating reagent such as boron tribromide or trichloride or according to any method known to those skilled in the art.

The compounds of the invention are useful in the treatment of epilepsy, epileptic seizures, seizure disorders, convulsions, especially intractable seizures.

Accordingly, in another embodiment, the invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use as a medicament.

In one aspect of its embodiment, the invention also provides a compound of formula (I) as defined above for use in the treatment and/or prevention of epilepsy, epileptic seizures, seizure disorders, convulsions, in particular refractory seizures. A compound or a pharmaceutically acceptable salt thereof is provided.

In a further embodiment, the invention provides a medicament as defined above for the manufacture of a medicament for the treatment and/or prevention of epilepsy, epileptic seizures, seizure disorders, convulsions, in particular for the treatment of refractory seizures. Uses of compounds of formula (I) or pharmaceutically acceptable salts thereof are provided. Seizures may be classified as refractory if the patient is unable to achieve a seizure-free period of 12 months or more with prior art treatment with two or more antiepileptic drugs at maximum tolerated doses. The International League Against Epilepsy (ILAE) defines drug-resistant epilepsy as “a well-tolerated, appropriately selected and used schedule of two AEDs (monotherapy or combination) to achieve sustained seizure-free periods”. It is defined as ``sufficient test failure''.

The methods of the invention involve administering to a mammal (preferably a human) suffering from the above-described condition or disorder a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition. include.

The compound may be in any suitable unit dosage form, including, but not limited to, unit dosage forms containing 1 to 2000 mg, preferably 1 to 1000 mg, more preferably 1 to 500 mg of active ingredient per unit dosage form. Administered as appropriate.

The term "treatment" as used herein includes curative treatment and prophylactic treatment.

"Curative" means efficacy in treating a current symptomatic episode of a disorder or condition.

"Prophylactic" means prevention of the occurrence or recurrence of a disorder or condition.

The term "epilepsy" as used herein refers to a chronic neurological condition characterized by unprovoked, recurrent epileptic seizures. Epileptic seizures are the expression of abnormal and excessive synchronized discharges of a series of brain neurons, and the clinical symptoms are sudden and transient. The term "epilepsy" as used herein may also refer to a disorder of brain function characterized by the periodic occurrence of seizures. Seizures can be "non-epileptic" when triggered in the normal brain by conditions such as high fever or exposure to toxins, or "epileptic" when provoked without obvious provocation.

The term "seizure" as used herein refers to a transient change in behavior due to the chaotic, synchronous, and rhythmic firing of a population of brain neurons.

A further aspect of the invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable diluent or carrier.

Activity in any of the above indications is, of course, determined by conducting suitable clinical trials in a manner known to those skilled in the art for the particular indication and/or in the design of clinical trials in general. be able to.

For treating diseases, compounds of formula (I) or their pharmaceutically acceptable salts may be used in effective daily dosages and administered in the form of pharmaceutical compositions.

Accordingly, another embodiment of the invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

To prepare a pharmaceutical composition according to the invention, one or more of the compounds of formula (I) or a pharmaceutically acceptable salt thereof are combined with a pharmaceutical diluent or a pharmaceutical diluent according to conventional pharmaceutical compounding techniques known to those skilled in the art. intimately mixed with the carrier.

Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, eg, oral, rectal, parenteral or intranasal.

Pharmaceutical compositions containing the compounds according to the invention can be administered, for example, orally, parenterally, ie intravenously, intramuscularly or subcutaneously, intrathecally, transdermally (patch), inhaled or intranasally.

Pharmaceutical compositions suitable for oral administration may be solid or liquid and may, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing gums, and the like.

For this purpose, the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions also contain binders such as microcrystalline cellulose, gum tragacanth or gelatin, disintegrants such as alginic acid, lubricants such as magnesium stearate, lubricants such as colloidal silicon dioxide, sucrose or saccharin. It may contain sweetening agents, or coloring agents, or flavoring agents such as peppermint or methyl salicylate.

The present invention also contemplates compositions that are capable of releasing active agents in a controlled manner.

Pharmaceutical compositions that can be used for parenteral administration are in conventional forms such as aqueous or oily solutions or suspensions commonly contained in ampoules, disposable syringes, glass or plastic vials or injection containers.

In addition to the active ingredient, these solutions or suspensions may also contain sterile diluents such as water for injection, saline, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, Antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffering agents such as acetates, citrates or phosphates, and osmotic pressure regulators such as sodium chloride or dextrose may optionally be included.

These pharmaceutical forms are prepared using methods routinely used by pharmacists.

The amount of active ingredient in a pharmaceutical composition can fall within a wide range of concentrations and depends on various factors such as the sex, age, weight and medical condition of the patient, and the method of administration. The amount of compound of formula (I) in a composition for oral administration is therefore at least 0.5% by weight and may be up to 80% by weight relative to the total weight of the composition.

According to the present invention, it has also been found that a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered alone or in combination with other pharmaceutically active ingredients. Non-limiting examples of such additional compounds that may be mentioned for use in combination with the compounds according to the invention include antivirals, antispasmodics (e.g. baclofen), antiemetics, antimanic mood stabilizers. , analgesics (e.g. aspirin, ibuprofen, paracetamol), narcotic analgesics, local anesthetics, opioid analgesics, lithium salts, antidepressants (e.g. mianserin, fluoxetine, trazodone), tricyclic antidepressants (e.g. , imipramine, desipramine), anticonvulsants (e.g., valproic acid, carbamazepine, phenytoin), schizophrenia drugs (e.g., risperidone, haloperidol), neuroleptics, benzodiazepines (e.g., diazepam, clonazepam), phenothiazines (e.g., Chlorpromazine), calcium channel blockers, amphetamines, clonidine, lidocaine, mexiletine, capsaicin, caffeine, quetiapine, serotonin antagonists, beta blockers, antiarrhythmics, triptans, ergot derivatives, and amantadine.

For oral compositions, the daily dosage ranges from 1 mg to 2000 mg of the compound of formula (I). Preferably the range is from 1 mg to 1000 mg, most preferably from 1 mg to 500 mg of the compound of formula (I).

In compositions for parenteral administration, the amount of compound of formula (I) present is at least 0.5% by weight and can be up to 33% by weight relative to the total weight of the composition. For preferred parenteral compositions, the dosage unit ranges from 1 mg to 2000 mg of a compound of formula (I).

The daily dose may fall within a wide range of dosage units of a compound of formula (I) and generally ranges from 1 to 2000 mg, preferably from 1 to 1000 mg. However, it should be understood that the specific dosage can be adapted to a particular case according to individual requirements, at the discretion of the physician.

SV2 protein binding compounds and labeled derivatives thereof provided by the present invention can be useful as standards and reagents in determining the ability of test compounds (e.g., potential pharmaceuticals) to bind to SV2 protein.

The labeled derivatives of ligands for SV2 proteins provided by the present invention may also be useful as radioactive tracers for positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT).

Therefore, the present invention aims to localize the SV2 protein in tissues for the discovery of potential medicines, in particular for the treatment and prevention of the conditions described herein, based on stronger binding to the SV2 protein. The labeled ligands are further provided as tools for screening chemical libraries for characterization as well as for characterizing purified SV2 proteins. SV2 proteins include SV2A, SV2B and SV2C, with SV2A being the binding site for the anti-seizure drug levetiracetam and its analogs. The SV2 isoforms SV2A, SV2B or SV2C can be derived from tissues of any mammalian species, including humans, rats or mice, especially the brain. Alternatively, the isoform can be a cloned version of any mammalian species, including human, rat and mouse, that is heterologously expressed and used in the assay. The screening method involves exposing brain membranes, such as mammalian or human brain membranes, or cell lines expressing SV2 proteins or fragments thereof, particularly SV2A and SV2C, but including SV2B, to the putative agent, and exposing the membrane or protein or fragment and the drug. incubating with a labeled compound of formula (I). The method further comprises determining whether binding of the compound of formula (I) to the protein is inhibited by the putative agent, thereby identifying the protein's binding partner. Thus, screening assays allow the identification of new drugs or compounds that interact with SV2 proteins. The invention also provides photoactivatable ligands for SV2 proteins.

Labeled ligands can also be used as a tool to assess the conformational state of the SV2 protein after solubilization, purification and chromatography. Labeled ligands can be labeled directly or indirectly. Examples of suitable labels include radioactive labels such as ³ H, fluorescent labels, enzymes, europium, biotin, and other conventional labels for this type of assay.

Labeled compounds of formula (I) are useful in this method as probes in assays for screening new compounds or agents that bind to SV2 proteins (SV2A, SV2B and SV2C). In such assay embodiments, the ligand may be used unmodified or may be attached in a variety of ways, e.g., covalently or non-covalently, with a moiety that directly or indirectly provides a detectable signal. It can be modified by a label, such as covalently attached. In any of these assays, the material can be labeled directly or indirectly. Direct labeling possibilities include, but are not limited to, radiolabels including [ ³ H], [ ¹⁴ C], [ ³² P], [ ³⁵ S] or [ ¹²⁵ I], peroxidase and alkaline phosphatase. Included are enzymes, as well as labels such as fluorescent labels that can monitor changes in fluorescence intensity, wavelength shift, or fluorescence polarization, including, but not limited to, fluorescein or rhodamine. Possibilities for indirect labeling include biotinylation of one component followed by binding to avidin coupled to one of the above-mentioned groups of labels, or the use of anti-ligand antibodies. When the compound is attached to a solid support, the compound may also include a spacer or linker. In order to identify agents or compounds that compete with or interact with labeled ligands according to the invention for binding to SV2 proteins (particularly SV2A and SV2C), intact cells containing SV2A or SV2C or the entire SV2 protein or fragments thereof; Cell fragments or membrane fragments can be used. The agent or compound may be incubated with the cells, membranes, SV2 proteins or fragments prior to, concurrently with, or subsequent to incubation with labeled levetiracetam or analogs or derivatives thereof. Assays can be modified or prepared in any available format, including high throughput screening (HTS) assays that monitor the binding of levetiracetam or derivatives or analogs thereof to SV2 proteins or fragments thereof. In many drug screening programs that test libraries of compounds, high-throughput assays are desirable to maximize the number of compounds investigated in a given period of time. Such screening assays may use cell-free or membrane-free systems, such as those that can be induced by intact cells, cell or membrane fragments, and purified or semi-purified proteins containing SV2. An advantage of assays using SV2 proteins and peptides or membrane fragments containing purified SV2 proteins and peptides is that cytotoxicity and/or bioavailability effects of the test compound can generally be ignored, and instead the assay The main emphasis then will be on the effect of the drug on the molecular target, as may be manifested, for example, in the inhibition of the binding between two molecules. The assay is adapted to detect the ability of a test agent or compound to inhibit the binding of a labeled ligand according to the invention to SV2 or an SV2 fragment, or the binding of labeled levetiracetam or a derivative or analog thereof to SV2 or an SV2 protein fragment. Can be assembled. Inhibition of complex formation can be detected by various techniques such as filtration assays, Flashplates (Perkin Elmer), scintillation proximity assays (SPA, GE). For high-throughput screening (HTS), scintillation proximity assays using biofilm-coated microspheres or biofilm-coated flashplates are powerful methods that do not require separation or washing steps.

A challenge that may be encountered in developing compounds for therapeutic use is that certain compounds (perpetrator drugs) may be co-administered with compounds of the invention (victim drugs). , the ability to induce CYP450 enzymes, particularly CYP3A4/5. Induction of such enzymes by offending drugs, if metabolized primarily by CYP450 enzymes, particularly CYP3A4/5, could affect the exposure of sacrificial drugs, thereby potentially altering their efficacy profile. . Therefore, it is desirable to develop compounds with limited potential for metabolism by CYP3A4/5 enzymes.

The contribution of CYP3A4/5 to the overall metabolism of compounds according to the invention was evaluated by calculating the ratio of human hepatocyte clearance in the absence and presence of a selective CYP3A4/5 inhibitor such as azamulin.

When tested in this assay according to the protocol described in this patent application, compounds according to the attached examples typically have a fraction metabolized by CYP3A4/5 (F _{m , CYP3A4/5} ) of less than 45%. and thus minimize the risk of drug-drug interactions when co-administered with CYP450 inducers.

Furthermore, it may be advantageous that the compounds according to the invention exhibit low intrinsic clearance.

Experimental Section Abbreviations/Reproducible Reagents Ac: acetyl ACN: acetonitrile Brine: saturated aqueous sodium chloride solution nBu: n-butyl tBu: tert-butyl Bz: benzoyl CV: column volume DCM: dichloromethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide Et: ethyl EtOH: ethanol Et ₂ O: diethyl ether EtOAc: ethyl acetate h: time HPLC: high pressure liquid chromatography LC: liquid chromatography LCMS: liquid chromatography mass spectrometry MeOH: methanol min. : minutes MTBE: methyl tert-butyl ether NMR: nuclear magnetic resonance iPrOH: isopropanol PTSA: p-toluenesulfonic acid RT: room temperature SFC: supercritical fluid chromatography THF: tetrahydrofuran TLC: thin layer chromatography

Analytical Methods All reactions involving air or moisture sensitive reagents were performed under nitrogen or argon atmosphere using dry solvents and glassware. Experiments requiring microwave irradiation are performed using a Biotage Initiator Sixty microwave oven upgraded with operating software version 2.0. The experiment is run to reach the required temperature as quickly as possible (maximum irradiation power: 400 W, no external cooling). Commercially available solvents and reagents were generally used without further purification, including anhydrous solvents when appropriate (generally the Sure-Seal™ product from Aldrich Chemical Company or AcroSeal™ from ACROS Organics). . Reactions were generally followed by thin layer chromatography, HPLC or mass spectrometry.

HPLC analysis is performed using an Agilent 1100 series HPLC system equipped with a Waters XBridge MS C18, 5 pm, 150 x 4.6 mm column. The gradient was from 100% solvent A (water/ACN/ammonium formate solution 85/5/10 (v/v/v)) to 100% solvent B (water/ACN/ammonium formate solution 5/85/10 (v/v/v)) in 6 minutes. v/v/v)), held at 100% B for 5 minutes. The flow rate is set at 8 mL/min for 6 minutes, then increased to 3 mL/min for 2 minutes and held at 3 mL/min for 3 minutes. Use a 1/25 split just before the API source. Chromatography is performed at 45°C. An ammonium formate solution (pH approximately 8.5) is prepared by dissolving ammonium formate (630 mg) in water (1 L) and adding 30% ammonium hydroxide (500 μL).

It will be apparent to those skilled in the art that if different analysis conditions are used, different retention times may be obtained for the LC data.

Mass spectrometry measurements in LCMS mode are performed as follows:
- For basic elution, the analysis is performed using:
A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (200-400 nm). Data are acquired with a full MS scan from m/z 70-800 in positive mode with basic elution. Reverse phase separation is carried out at 45° C. using a Waters Acquity UPLC BEHC18 1.7 μm (2.1×50 mm) column with basic elution. Gradient elution is performed with water/ACN/ammonium formate (95/5/63 mg/L) (solvent A) and ACN/water/ammonium formate (95/5/63 mg/L) (solvent B). Injection volume: 1 μL. Total flow rate of MS.

- In case of acidic elution, analysis is carried out using:
A QDA Waters simple quadrupole mass spectrometer is used for LCMS analysis. The spectrometer is equipped with an ESI source and a UPLC Acquity Hclass with a diode array detector (200-400 nm). Data are acquired with a full MS scan from m/z 70-800 in positive mode with acidic elution. Reverse phase separation is performed at 45° C. using a Waters Acquity UPLC HSS T3 1.8 μm (2.1×50 mm) column with acidic elution. Gradient elution is performed with water/ACN/TFA (95/5/0.5 mL/L) (solvent A) and ACN (solvent B). Injection volume: 1 μL. Total flow rate of MS.

The crude material may be purified by normal phase chromatography, reverse phase chromatography (acidic or basic), chiral separation or recrystallization.

Conventional reverse phase chromatography is performed using a silica gel column (100:200 mesh silica gel, or a Puriflash®-50SIHC-JP column from Interchim).

Preparative reverse phase chromatography is performed as follows:
- For LCMS purification, use LCMS purification (basic mode, LCMS prep) using an SQD or QM Waters triple quadrupole mass spectrometer. The spectrometer is equipped with an ESI source and a Prep LC controller Waters quaternary pump with a diode array detector (210-400 nm).

MS parameters: ESI capillary voltage 3kV. Cone and extractor voltage 10. Source block temperature 120℃. Desolvation temperature: 300°C. Cone gas flow rate 30L/hour (nitrogen), desolvation gas flow rate 650L/hour. Data are acquired with a full MS scan from m/z 100 to 700 in positive mode with acidic or basic elution.

LC parameters: Reverse phase separation is performed at room temperature using an XBridge prep OBD C18 column (5 μm, 30×50 mm) (basic elution). Gradient elution is performed using water (solvent A), ACN (solvent B), ammonium bicarbonate aqueous solution 8 g/L + 500 μL/L NH ₄ OH 30% (solvent C) (pH approximately 8.5). HPLC flow rate: 35 mL/min to 60 mL/min, injection volume: 1 mL. Set the split ratio to +/-1/6000 for the MS.

Products were generally dried under vacuum before final analysis and before being subjected to biological testing.

NMR spectra are recorded using a BRUKER AVANCE III Ultrashield Nanobay 400MHz NMR spectrometer equipped with a Windows 7 workstation running Bruker Topspin 3.2 software and a 5mm BBI S1 equipped with a Z-gradient probe head. . Some NMR spectra were recorded using a BRUKER AVANCE III HD Ascend 500MHz NMR spectrometer equipped with a Windows 7 workstation running Bruker Topspin 3.2 pl2 software and a 5mm Prodigy BBO 500 S1 cryoprobe. I will. Compounds are tested in d ₃ -chloroform or d ₆ -DMSO solutions at a probe temperature of 300K. The instrument locks on the deuterium signal of the solvent used. Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) used as internal standard.

Compound names are generated by Accelrys Draw 4.0 or Biovia Draw 16.1.

The following examples illustrate how compounds encompassed by formula (I) can be synthesized. They are provided for illustrative purposes only and are not intended and should not be construed as limiting the invention in any way. Those skilled in the art will appreciate that routine changes and modifications to the following examples can be made without departing from the spirit or scope of the invention.

Intermediate A. Synthesis of 2-hydroxy-3-(2,2,2-trifluoroethyl)-2H-furan-5-one II

A. 1. Sodium; Synthesis of 4,4,4-trifluoro-1-hydroxy-butane-1-sulfonate I 4,4,4-trifluorobutyraldehyde (CAS: 406-87-1, 1.0 equivalent, 12.75 g , 101 mmol) at 0° C., an aqueous solution (25 mL) of sodium bisulfite (1.0 eq., 10.50 g, 101 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The precipitate was filtered and washed with cold methanol (500 mL) at 0°C. The resulting solid was dried under high vacuum at 40° C. for 16 hours to give sodium; 4,4,4-trifluoro-1-hydroxy-butane-1-sulfonate I (15.4 g, 66.9 mmol) as a white solid. was obtained and used in the next step without further purification.
Yield: 66%

A. 2. Synthesis of 2-hydroxy-3-(2,2,2-trifluoroethyl)-2H-furan-5-one II Glyoxylic acid in a mixture of water (6 mL) and 1,4-dioxane (6 mL) Sodium; Fluoro-1-hydroxy-butane-1-sulfonate I (1.0 eq., 3.0 g, 13.0 mmol) and hydrochloric acid (2.0 eq., 2.2 mL, 26 mmol) were added at room temperature. The mixture was stirred at 110° C. for 20 hours, then cooled to room temperature. Water was added to the mixture and the aqueous layer was extracted using MTBE (3 times). The combined organic layers were washed with brine, dried over _MgSO4 , filtered and evaporated to dryness to give 2-hydroxy-3-(2,2,2-trifluoroethyl)-2H-furan-5- On II (900 mg, 4.5 mmol, estimated purity 90%) was obtained and used in the next step without further purification.
Yield: 34%

Following the same two-step procedure starting from 4,4-difluoropentanal (CAS: 1546331-97-8), 3-(2,2-difluoropropyl)-2-hydroxy-2H-furan-5-one II -A was prepared.
Yield: 40%

Following the same two-step procedure starting from 5,5,5-trifluoropentanal (CAS:250253-47-5), 2-hydroxy-3-(3,3,3-trifluoropropyl)-2H- Furan-5-one III was prepared.
Yield: 55% (1st stage) and 73% (2nd stage).

2-Hydroxy-3-propyl-2H-furan-5-one III-A is commercially available (CAS:78920-10-2) or can be prepared following the same procedure starting from butyraldehyde.

3-(2,2-difluorocyclopropyl)-2-hydroxy-2H-furan-5-one III-B was prepared from 2-(2,2-difluorocyclopropyl)acetaldehyde following a slightly modified procedure. :

To a solution of a mixture of morpholines (1.1 eq., 1.07 g, 676.0 mmol) in heptane (55 mL) was added glyoxylic acid (0.95 eq., 965 mg, 614.5 mmol) at 0°C, and the mixture was incubated at 40°C for 2 hours. Stir for hours. The mixture was then cooled to room temperature, 2-(2,2-difluorocyclopropyl)acetaldehyde (CAS: 1823961-57-4, 1.1 eq., 1.07 g, 676.0 mmol) was added and the mixture was heated at 40°C. The mixture was stirred for 16 hours. Hydrochloric acid (1.75 equivalents, 1075.5 mmol, 12.2 mL, 36.5 wt%) was added to the mixture cooled to 0° C., and the mixture was stirred at room temperature for 2 hours. Dichloromethane was then evaporated under vacuum at 25° C. and water was added to the resulting mixture. The aqueous layer was washed with heptane (3 times) and a saturated aqueous solution of Na ₂ CO ₃ was added until pH=6-7. The aqueous layer was extracted with ethyl acetate (3 times) and the combined organic layers were dried over _MgSO4 , filtered and evaporated to dryness to give 3-(2,2-difluorocyclopropyl)-2- Hydroxy-2H-furan-5-one III-B (1.5 g, 7.7 mmol, 90% by weight, estimated purity based on ¹⁹ F-NMR) was obtained as a brown oil, which was used directly in the next step.
Yield: 69%

B. Synthesis of [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V

B. 1 Synthesis of 2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole IV 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine ( Bromoacetone (1.0 equivalent, 4.2 mL, A solution of 46.2 mmol (purity 97%) in DMF (5 mL) was added dropwise at 100°C. The reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature (RT) and the solvent was evaporated to dryness under high vacuum to give a brown oil. The crude product was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column with a gradient of 0% to 10% methanol in dichloromethane through 14 CV) and the pure fractions were evaporated to dryness to give 2-(methoxy methyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole IV (5.0 g, 25.11 mmol) was obtained as a yellow/orange solid.
Yield: 52%

B. 2 Synthesis of [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V In a sealed tube, 2-(methoxymethyl)-6 -Methyl-imidazo[2,1-b][1,3,4]thiadiazole IV (1.0 eq., 5.0 g, 25.1 mmol), paraformaldehyde (6.0 eq., 4.50 g, 150 mmol) and Aqueous hydrochloric acid (4N) solution (2 eq., 12.55 mL, 50.2 mmol) was mixed in 1,4-dioxane (12.5 mL). The mixture was stirred at 100° C. for 18 hours, then the crude mixture was warmed to room temperature and a saturated aqueous solution of NaHCO ₃ was added until pH=6-7. The aqueous layer was extracted with ethyl acetate (3 times) and the combined organic layers were washed with brine, dried over _MgSO4 , filtered and evaporated to dryness. The crude product was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column with a gradient of 0% to 5% methanol in dichloromethane through 12 CV). The purest fractions were evaporated to dryness to yield [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V (4. 0 g, 18.57 mmol) as a white solid.
Yield: 74%

C. Synthesis of [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII

C. 1. Synthesis of 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI 5-(methoxymethyl)-1,3,4-thiadiazole-2 -To a solution of amine (CAS: 15884-86-3, 1.0 eq., 6.5 g, 45 mmol) in DMF (100 mL) was added 3-bromo-1,1-difluoro-propan-2-one (CAS: 883233- A solution of 85-0, 1.05 equivalents, 8.1 g, 47 mmol) in DMF (5 mL) was added dropwise at 100°C. The reaction mixture was heated at 100° C. for 3 hours and completed by LC/MS. A saturated aqueous solution of NaHCO ₃ was added and the organic layer was extracted with ethyl acetate (3 times). The combined organic layers were washed with water (5 times), dried over _MgSO4 , filtered and evaporated to dryness to give a brown solid (7.6g). The crude product was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column with a gradient of 0% to 5% methanol in dichloromethane through 12 CV) and the pure fractions were combined and evaporated under high vacuum. 6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI (3.95 g, 17.8 mmol) was obtained as an orange solid.
Yield: 40%

C. 2. Synthesis of [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII In a sealed tube, 6-(difluoromethyl)- 2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI (1.0 equivalents, 3.95 g, 18.0 mmol), paraformaldehyde (6.0 equivalents, 3.24 g, 108 mmol) and aqueous hydrochloric acid (2N) (0.9 eq., 8.1 mL, 16.2 mmol) were mixed in 1,4-dioxane (8 mL). The mixture was stirred at 100° C. for 3.5 hours and the reaction was confirmed by LC/MS. The crude mixture was warmed to room temperature and a saturated aqueous solution of NaHCO ₃ was added until pH=6-7. The aqueous layer was extracted with ethyl acetate (3 times) and the combined organic layers were washed with brine, dried over _MgSO4 , filtered and evaporated to dryness. The crude product was purified by flash chromatography Biotage Isolera Four (100 g KP-SNAP silica gel column with a gradient of 0% to 10% methanol in dichloromethane over 15 CV) to give a yellow oil (3 g), which was purified by reverse phase HPLC ( Purified twice by KROMASIL-Eternity XT C ₁₈ 10 μm/20/80/0.1 to 50/50/0.1 ACN/H ₂ O/NH ₄ OH gradient). The purest fractions were evaporated to dryness to give [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII ( 2 g, 8.02 mmol) as a white solid.
Yield: 45%

D. [6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII-A

D. 1. Synthesis of 6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI-A 5-(methoxymethyl)-1,3, A solution of 4-thiadiazol-2-amine (1 equivalent, 2.0 g, 13.7 mmol) in DMF (30 mL) was added with 2-chloro-1-(1-fluorocyclopropyl)ethanone (CAS: 151697-21-1), A solution of 1.05 eq., 1.97 g, 14.4 mmol) in DMF (2 mL) was added dropwise at 10°C. The reaction mixture was heated at 100° C. for 2 hours and 30 minutes, then a saturated aqueous solution of NaHCO ₃ was added and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers were washed with water (5 times), dried over _MgSO4 , filtered and evaporated to dryness to give a brown oil. The crude product was purified by reverse phase preparative HPLC Gilson (YMC Triart C18 80 x 204 - 10 μm - 500 g - gradient ACN/H ₂ O 40/60 to 95/05) to give 6-(1-fluorocyclopropyl) -2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole VI-A (1.16 g, 5.10 mmol) was obtained as a beige solid.
Yield: 37%

D. 2. Synthesis of [6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII-A 6-(1-fluoro cyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole (VI-A, 1 eq., 395 mg, 1.74 mmol) and paraformaldehyde (6 eq., 312.8 mg , 10.43 mmol) in 1,4-dioxane (1.7 mL) was added hydrochloric acid (4 equivalents, 1.82 g, 6.95 mmol, 4 mol/L), and the mixture was stirred at 100° C. for 1 hour. A saturated aqueous solution of NaHCO ₃ was added and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers were dried over _MgSO4 , filtered and evaporated to dryness to give a brown oil, which was purified by SFC (PREP 600, column P4VP 50 x 174-5 μm-200 g, co-solvent MeOH 5%). and [6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII-A (250 mg, 0.92 mmol ) was obtained as a beige solid.
Yield: 53%

Example 1 - [[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole Synthesis of -5-one 1

1.1 Synthesis of 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII.
Suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-33, 46 g, 2.4 mol, 1 eq.) in 1,2-dimethoxyethane (6 L) 3-bromo-1,1,1-trifluoroacetone (CAS: 431-35-6, 478 g, 2.5 mol, 1.05 equivalents) is added to the solution at 20°C. The reaction mixture is heated to 80° C. until maximum conversion (<24 hours). Water (4 L) is added to the reaction mixture at 32° C. and the expected compound crystallizes from the reaction mixture. The crystalline suspension was cooled to 10°C to complete the crystallization process, filtered and the crystalline precipitate was washed with water (1.5L) to yield 266g of pure 2-(methoxymethyl)-6. -(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII is obtained.
Yield: 47%

1.2 Synthesis of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol IX.
2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole VIII (10 g, 42.16 mmol, 1 eq.), formaldehyde (16 g, 421.6 mmol, 10 eq.) and hydrochloric acid (37%, 8.2 ml, 2 eq.) in sulfolane (250 ml). Heat the reaction mixture at 110° C. overnight. Water (500 ml) is added and the mixture is heated at 50° C. for 2 hours. The solvent is then removed under reduced pressure. The residue was purified by chromatography on silica gel (gradient; eluent: CH ₂ Cl ₂ /MeOH/NH ₄ OH 100/0/0 to 99/1/0.1) to give 6.5 g of [2- (Methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol IX is obtained as a yellow solid.
Yield 58%

1.3 Synthesis of 5-(azidomethyl)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole X.
[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol IX (1.33 g, 4.98 mmol, 1 eq.) N,N-diisopropylethylamine (3.22 g, 24.88 mmol, 5 eq.) and methanesulfonyl chloride (0.855 g, 7.47 mmol, 1.5 eq.) were added slowly to a dichloromethane (30 ml) solution at 0°C. I add. Sodium azide (0.485 g, 7.47 mmol, 1.5 eq.) suspended in DMF (5 ml) is added at 0° C., then warmed to room temperature and the reaction mixture is stirred overnight. After hydrolysis (H ₂ O) and extraction with diethyl ether, the combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure to yield 1.45 g of 5-(azidomethyl)-2-( methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole X is obtained.
Yield: 100%

Following the same procedure starting from [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V, 5-(azidomethyl)-2 -(Methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole XI is prepared.
Yield: 62%

1.4 Synthesis of 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XII.
5-( _azidomethyl )-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole X ( Triphenylphosphine (1.31 g, 4.98 mmol, 1 eq.) is added to a suspension of 1.45 g, 4.98 mmol, 1 eq.) at room temperature. The reaction mixture is stirred at room temperature for 60 hours. The solvent is evaporated under reduced pressure, water is added to the residue and the solution is acidified to pH 2 using 5N aqueous HCl and then extracted with Et ₂ O (1×50 ml). The aqueous layer was basified (pH 8) by adding aqueous Na ₂ CO ₃ and extracted using dichloromethane (2 x 50 ml), and the accumulated organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure. Thus, 1.16 g of 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XII is obtained.
Yield: 88%

Following the same procedure starting from 5-(azidomethyl)-2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole XI, [2-(methoxymethyl)- Prepare 6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XIII. Purification of the crude mixture was carried out by reverse phase preparative HPLC (KROMASIL-Eternity XT C ₁₈ 10 μm/20/80/0.1 to 95/5/0.1 ACN/H ₂ O/NH ₄ OH gradient).
Yield: 74%

1.5 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H -Synthesis of pyrrol-5-one 1 2-hydroxy-3-propyl-2H-furan-5-one III-A (CAS: 78920-10-2, 160.8 mg, 1.127 mmol, 1 equivalent) and 1- Dry [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XII (300 mg, 1.127 mmol, 1 eq.) Dissolve in methanol (3 ml) and stir the mixture at room temperature for 3 hours and 30 minutes, then cool at 0°C. Sodium borohydride (42.8 mg, 1.127 mmol, 1 eq.) is added and the reaction is stirred at 0° C. for 1 hour. 0.5 ml of acetic acid is added and the mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure, water and dichloromethane are added to the residue and the mixture is extracted three times with dichloromethane. The combined organic layers are dried over _MgSO4 , filtered and evaporated under reduced pressure. The residue (327 mg) was purified by chromatography on silica gel (CH2Cl2/MeOH/ _NH4OH 99/1 _/ 0.1) and further recrystallized from heptane/diethyl ether (80/20 ₎ . , 127.6 mg of pure 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3 -propyl-2H-pyrrol-5-one 1 is obtained.
Yield: 30%

Following the same procedure starting from 2-hydroxy-3-(2,2,2-trifluoroethyl)-2H-furan-5-one II, 1-[[2-(methoxymethyl)-6-(trifluoroethyl) Preparation of methyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoroethyl)-2H-pyrrol-5-one 2 do.
Yield: 30%

Following the same procedure starting from 2-hydroxy-3-(3,3,3-trifluoropropyl)-2H-furan-5-one III, 1-[[2-(methoxymethyl)-6-(trifluoropropyl) Preparation of methyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoropropyl)-2H-pyrrol-5-one 3 do.
Yield: 34%

[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XIII and 2-hydroxy-3-propyl-2H-furan-5- Following the same procedure starting from III-A (CAS:78920-10-2), 1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4 ]Thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one 4 is prepared.
Yield: 30%

1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole- Synthesis of 5-one 5

2.1 Synthesis of tert-butyl[5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate XIV.
A suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine (CAS: 15884-86-33, 100 g, 0.69 mol, 1 eq) in dichloromethane (1 L) was added with di- Tert-butyl carbonate (132 g, 0.76 mol, 1.1 eq.) and N,N-dimethylamino-pyridine (8.35 g, 0.069 mol, 0.1 eq.) are added sequentially and each at once at room temperature. After stirring overnight at room temperature, the reaction mixture is washed with 1N HCl (pH 5) to remove N,N-dimethylaminopyridine. The solvent was removed under reduced pressure and the residue was recrystallized from diisopropyl ether to yield 148.9 g of pure tert-butyl[5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate. Get XIV.
Yield: 88%

2.2 Synthesis of {2-[(tert-butoxycarbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3(2H)-yl}acetic acid XV.
To a solution of tert-butyl[5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate XIV (360 g, 1.47 mol, 1 eq.) in tetrahydrofuran (3 L) was added iodoacetic acid (409.3 g, 2.2 mol, 1.5 eq.) are added in one portion at room temperature. Sodium hydride (52.8 g, 2.2 mol, 1.5 eq.) is then added in portions at room temperature within 30 minutes. The reaction mixture is heated at 60° C. overnight and the solvent is evaporated under reduced pressure. Water is added to the residue and the solution is acidified to pH=2 using 6N aqueous HCl and then extracted using CH ₂ Cl ₂ . The organic layer was washed with 10% aqueous sodium thiosulfate and evaporated to dryness to yield 455.7 g of {2-[(tert-butoxy-carbonyl)imino]-5-(methoxymethyl)-1,3,4- Thiadiazol-3(2H)-yl}acetic acid XV is obtained, which is used directly in the next step without further purification.
Yield: 90%

2.3 Synthesis of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole XVI.
{2-[(tert-butoxycarbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3(2H)-yl}acetic acid XV (418 g, 1.38 mol, 1 eq.) in acetonitrile ( To the 2.5 L) solution, triethylamine (278.9 g, 2.76 mol, 2 eq.) is slowly added one after another at room temperature, followed by phosphorus oxychloride (633.9 g, 4.13 mol, 3 eq.). The reaction mixture is heated at 80° C. for 1 hour. After the reaction is complete, water (2.2 L) is slowly and carefully added at 50°C. The reaction mixture was extracted with dichloromethane (2 x 1.2 L), the combined organic layers were washed with aqueous NaOH/NaCl (1.4 L of saturated NaCl solution + 400 ml of 2N NaOH), dried over _MgSO4 , Filter and concentrate under reduced pressure. Recrystallization of the residue from acetonitrile/water (1/1) yielded 99.8 g of pure 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole. Get XVI.
Yield: 36%

2.4 Synthesis of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde XVII.
To dimethylformamide (5 ml) cooled to 0°C is added phosphorus oxychloride (2.75 ml, 3 eq.) very slowly. Increase temperature to 50°C. The reaction mixture was heated to 60° C. and then 2 g of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole XVI (2 g, 9.82 mmol, 1 eq.) Add little by little over .5 hours. Pour the reaction mixture onto ice/water mixture. Filter the precipitate and wash with water. The residue was dried under vacuum at 40° C. overnight to give 1.8 g of 6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde XVII. is obtained as a solid.
Yield: 79%

2.5 Synthesis of [6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-methanol XVIII.
6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde XVII (2.97 g, 12.94 mmol, 1 eq) in ethanol (80 ml) Dissolve, cool at 0°C and add sodium borohydride (578 mg, 15.53 mmol, 1.2 eq.) portionwise at 0°C. The reaction mixture is stirred at room temperature overnight, then cooled to 0° C. and saturated aqueous NH ₄ Cl (100 ml) is added. The organic solvent was evaporated under reduced pressure and the precipitate was filtered and dried under vacuum at 20°C to give 1.99 g of [6-chloro-2-(methoxymethyl)imidazo[2,1-b][1, 3,4]thiadiazol-5-yl]methanol XVIII is obtained.
Yield: 66%

2.6 Synthesis of 5-(azidomethyl)-6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole XIX.
[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol N,N-diisopropylethylamine (10.7 mmol, 5 eq.) and methanesulfonyl chloride (0.368 g, 3.21 mmol, 1.5 eq.) are added slowly one after another to the solution (0.5 ml) at 0°C. Sodium azide (0.209 g, 3.21 mmol, 1.5 eq.) suspended in DMF (5 ml) is added at 0° C., then warmed to room temperature and the reaction mixture is stirred overnight. After hydrolysis (H ₂ O) and extraction with diethyl ether, the combined organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure to yield 434 mg of 5-(azidomethyl)-6-chloro-2 -(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole XIX is obtained, which is used in the next step without further purification.
Yield: 78%

2.7 Synthesis of [6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XX THF/H ₂ O (7.5 ml/0 5-(azidomethyl)-6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole XIX (0.434 g, 1.68 mmol, 1 eq) in .75 ml) Triphenylphosphine (0.438 g, 1.68 mmol, 1 eq.) is added to the suspension at room temperature. The reaction mixture is stirred at room temperature for 15 hours. The solvent is evaporated under reduced pressure, water is added to the residue and the solution is acidified to pH 2 using 5N aqueous HCl and then extracted with Et ₂ O (1×50 ml). The aqueous layer was basified (pH 8) by adding aqueous Na ₂ CO ₃ and extracted using dichloromethane (2 x 50 ml), and the accumulated organic layers were dried over MgSO ₄ , filtered and evaporated under reduced pressure. Thus, 0.34 g of 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XX is obtained.
Yield: 87%

2.8 1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- Synthesis of 2-hydroxy-3-(2,2,2-trifluoroethyl)-2H-furan-5-one (340 mg, 1.87 mmol, 1 equivalent) and 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine XX (434 mg, 1.87 mmol, 1 eq. ) is dissolved in dry methanol (10 ml) and the mixture is stirred at room temperature overnight and then cooled to 0°C. Sodium borohydride (77 mg, 2.03 mmol, 1.08 eq.) is added and the reaction is stirred at 0° C. for 1 hour. 1 ml of acetic acid is added and the mixture is stirred at room temperature for 1 hour. The solvent is evaporated under reduced pressure, water and dichloromethane are added to the residue and the mixture is extracted three times with dichloromethane. The combined organic layers are dried over _MgSO4 , filtered and evaporated under reduced pressure. The residue (800 mg) was purified by flash chromatography on silica gel (CH ₂ Cl ₂ /MeOH 98/2) and further recrystallized from acetonitrile to give 119 mg of pure 1-[[6-chloro-2- (methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoroethyl)-2H-pyrrol-5-one 5 get.
Yield: 16%

Following the same procedure starting from 2-hydroxy-3-propyl-2H-furan-5-one III-A (CAS:78920-10-2), 1-[[6-chloro-2-(methoxymethyl)imidazo [2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one 6 is prepared.
Yield: 50%

Following the same procedure starting from 2-hydroxy-3-(3,3,3-trifluoropropyl)-2H-furan-5-one III, 1-[[6-chloro-2-(methoxymethyl)imidazo[ 2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoropropyl)-2H-pyrrol-5-one 7 is prepared.
Yield: 24%

1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole-5 -Synthesis of On8

3.1. Synthesis of hexamethylenetetramine salt XXI [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol VII (1.0 equivalent, Thionyl chloride (1.2 eq., 287 mg, 2.4 mmol) was added to a solution of a mixture of 500 mg, 2.0 mmol) in dichloromethane (10 mL) at 0.degree. The reaction was stirred at 0° C. for 10 minutes, then at room temperature for 1 hour. The crude mixture was evaporated to dryness and the resulting adhesive was solubilized in dichloromethane (10 mL) before hexamethylenetetramine (3.0 eq., 852 mg, 6.0 mmol) was added. The reaction was then stirred at 35 °C for 2 h, cooled to 0 °C, filtered, and washed with cold dichloromethane to give XXI (900 mg, 1.87 mmol, estimated purity 85%) as a beige solid, This was used in the next step without further purification.
Yield: 93%

Preparing hexamethylenetetramine salt XXII following the same procedure starting from [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V do.
Yield: quantitative

3.2. Synthesis of [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine hydrochloride XXIII Hexamethylenetetramine salt XXI (1.0 Hydrochloric acid (4.5 eq., 914 mg, 9.0 mmol) was added to a solution of a mixture of methanol (5 mL) at room temperature. The reaction was stirred at 45° C. for 1 hour and the mixture was filtered. The resulting filtrate was then evaporated to dryness to give [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine; The hydrochloride salt XXIII (900 mg, 1.74 mmol, estimated purity 55%) was obtained as an impure beige solid, which was used in the next step without further purification.
Yield: quantitative

Following the same procedure starting from hexamethylenetetramine salt XXII, [2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine hydrochloride XXIV Prepare.
Yield: 55%

3.3.1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H -Synthesis of pyrrol-5-one 8 [6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine hydrochloride XXIII(1 2-hydroxy-3-propyl-2H-furan-5-one III-A (3.0 eq., 241 mg, 1.44 mmol, ¹ H NMR purity 85) %) and sodium hydroxide (2.0 eq., 39 mg, 0.96 mmol) in methanol (2 mL) was stirred at room temperature for 2 hours. Sodium borohydride (2 eq., 36 mg, 0.96 mmol) was added to the cooled solution at 0° C. and the mixture was stirred at 0° C. for 1 hour. Acetic acid (5.0 eq., 144 mg, 2.4 mmol) was then added and the mixture was stirred at room temperature for 3 hours. The crude mixture was evaporated to dryness to give an orange adhesive, which was analyzed by reverse phase preparative HPLC (KROMASIL-Eternity XT C ₁₈ 10 μm/30/70/0.1 to 60/40/0.1 ACN/ H ₂ O/NH ₄ OH gradient) to give 1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5- [yl]methyl]-3-propyl-2H-pyrrol-5-one 8 (42 mg, 0.12 mmol) was obtained as a beige solid.
Yield: 24%

1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoro Synthesis of ethyl)-2H-pyrrol-5-one 9

4.1. Synthesis of tert-butyl (4S)-2-oxo-4-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXV (4S)-4-(2,2,2-trifluoroethyl) Acetonitrile ( Di-tert-butyl carbonate (1.2 eq., 48 g, 213 mmol) was added to the solution (900 mL) at 0°C. The mixture was then warmed to room temperature and stirred for 4 hours. The solvent was evaporated under vacuum and water was added to the resulting mixture. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with brine, dried over _MgSO4 , filtered and evaporated to dryness to give a yellow oil.

The crude mixture was purified by normal phase flash chromatography Biotage Isolera Four (100 g of SNAP SiO ₂ with a gradient of 0% to 5% methanol in DCM through 12 CV). The purest fractions were evaporated to dryness to yield tert-butyl (4S)-2-oxo-4-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXV (24.5 g, 91. 5 mmol) was obtained as a white solid.
Yield: 51%

The following compounds were prepared following the same procedure.

4.2. Synthesis of tert-butyl (4S)-2-oxo-3-phenylceranyl-4-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXVI tert-butyl (4S)-2-oxo- To a solution of 4-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXV (1 eq., 10 g, 37.4 mmol) in tetrahydrofuran (250 mL) was added lithium bis(trimethylsilyl)amide (2 eq., 52 mL, 75.4 mmol, 1.45 mol/L) was added at -78°C and the mixture was stirred at -78°C for 1 hour. A solution of phenylselenenyl chloride (1.1 eq., 8.0 g, 41.7 mmol) in tetrahydrofuran (85 mL) was then added at -78°C and the mixture was stirred at -78°C for 1 hour. Water was then added to the stirred solution and the aqueous layer was extracted with ethyl acetate (3x), dried over _MgSO4 , filtered and evaporated to dryness to give a brown oil (15g), which was Purified by phase flash chromatography Biotage Isolera Four (340 g of SNAP SiO ₂ with a gradient of 10% to 20% ethyl acetate in heptane over 12 CV). The purest fractions were evaporated to dryness to yield tert-butyl(4S)-2-oxo-3-phenylselanyl-4-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXVI ( 6.2 g, 14 mmol) were obtained as a clear yellow oil.
Yield: 38%

The following compounds were prepared following the same procedure.

4.3. Synthesis of (4S)-3-phenylselanyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one XXVII tert-butyl(4S)-2-oxo-3-phenylselanyl-4- To a solution of a mixture of (2,2,2-trifluoroethyl)pyrrolidine-1-carboxylate XXVI (1 eq., 6.2 g, 15 mmol) in dichloromethane (150 mL) was added trifluoroacetic acid (14 eq., 15 mL, 200 mmol). It was added at 0° C. and the mixture was stirred at room temperature for 30 minutes. The mixture was evaporated to dryness, diluted with water and neutralized with NaHCO ₃ solid until pH=6-7. The organic layer was extracted with ethyl acetate (3 times), dried over _MgSO4 , filtered and evaporated to dryness to yield (4S)-3-phenylceranyl-4-(2,2,2- Trifluoroethyl)pyrrolidin-2-one XXVII (4.5 g, 14 mmol) was obtained as a white solid. The product was used directly in the next step without further purification. Yield: 95%

The following compounds were prepared following the same procedure.

4.4. (4S)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-phenylceranyl-4 Synthesis of -(2,2,2-trifluoroethyl)pyrrolidin-2-one XXVIII p-toluenesulfonic acid monohydrate (0.7 equivalents, 1.3 g, 6.8 mmol) and [2-(methoxy methyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol V (1 equivalent, 2 g, 9.37 mmol) and 3-phenylselanyl-4- A solution of a mixture of (2,2,2-trifluoroethyl)pyrrolidin-2-one XXVII (1 eq., 3 g, 9.31 mmol) in sulfolane (95 ml) was stirred at 130° C. for 16 hours. The mixture was poured into water and a saturated aqueous solution of NaHCO ₃ was added until pH=6-7. The organic layer was extracted using MTBE (twice). The combined organic layers were washed with water (3x), dried over _MgSO4 , filtered and evaporated to dryness to give a brown oil. The brown oil was purified by preparative LC YMC Triart C18 (80×204-10 μm-500 g, gradient 60% to 90% ACN in water) to give (4S)-1-[[2-(methoxymethyl)-6- Methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-phenylceranyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one XXVIII (450 mg, 0.82 mmol) was obtained as a brown oil.
Yield: 9%

The following compounds were prepared following the same procedure.

4.5. 1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoro Synthesis of (4S)-1-[[2-(methoxymethyl)-6-methyl-] in a mixture of methanol (5.5 ml) and water (1.1 mL). imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-phenylceranyl-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one XXVIII( To a solution of sodium periodate (9 eq., 1.6 mg, 7.48 mmol) was added at room temperature. The reaction was stirred at room temperature for 30 minutes. A saturated aqueous solution of NH ₄ Cl was then added to the mixture and the aqueous layer was extracted with EtOAc (3 times). The combined organic layers were dried over _MgSO4 , filtered, and evaporated to dryness to give a yellow oil, which was purified by reverse phase flash chromatography under neutral conditions on the Biotage Isolera Four (5% to 95% ACN in water through 12 CV). Purified by gradient C18 SNAP 30g gel column). The purest fraction was directly lyophilized to yield 1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl] -3-(2,2,2-trifluoroethyl)-2H-pyrrol-5-one 9 (71 mg, 0.1970 mmol) was obtained as a white solid.
Yield: 23%

The following compounds were prepared following the same procedure.

1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- Trifluoroethyl)-2H-pyrrol-5-one 10 was prepared starting from XXVIII-A.
Yield: 45%

1-[[6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2 ,2-trifluoroethyl)-2H-pyrrol-5-one 11 was prepared starting from XXVIII-B.
Yield: 9%

3-(2-chloro-2,2-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole -5-yl]methyl]-2H-pyrrol-5-one 12 was prepared starting from XXVIII-C.
Yield: 9%

1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro Propyl)-2H-pyrrol-5-one 13 was prepared starting from XXVIII-D.
Yield: 53%

1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- Trifluoropropyl)-2H-pyrrol-5-one 14 was prepared starting from XXVIII-E.
Yield: 52%

3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl] Methyl]-2H-pyrrol-5-one 15 was prepared starting from XXVIII-F.
Yield: 41%

1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2-difluoropropyl )-2H-pyrrol-5-one 16 was prepared starting from XXVIII-G.
Yield: 14%

3-[(1R)-2,2-difluorocyclopropyl]-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole -5-yl]methyl]-2H-pyrrol-5-one 17A and 3-[(1S)-2,2-difluorocyclopropyl]-1-[[2-(methoxymethyl)-6-(trifluoromethyl) ) Synthesis of imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-2H-pyrrol-5-one 17B

5.1.3-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole Synthesis of -5-yl]methyl]-2H-pyrrol-5-one 17 [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole- 3-(2,2-difluorocyclopropyl)-2-hydroxy-2H-furan- was added to a solution of 2-propanol (12 mL) of 5-yl]methanamine 5-one III-B (1 eq., 500 mg, 2.44 mmol, 80 wt%) was added at room temperature and the reaction was stirred at room temperature for 1 hour. An aqueous solution (3.5 mL) of sodium borohydride (1 eq., 92 mg, 2.44 mmol) was then added to the mixture at room temperature, and the reaction was stirred at room temperature for 2 hours. An additional amount of sodium borohydride (1 eq., 92 mg, 2.44 mmol) was then added to the mixture and the reaction was stirred at room temperature for 15 minutes. A third amount of sodium borohydride (1 eq., 92 mg, 2.44 mmol) was added followed by acetic acid (35 eq., 5 mL, 87.08 mmol) and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of NaHCO ₃ was added to the mixture cooled to 0° C., and the aqueous layer was extracted using MTBE (twice). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness (max. 25° C.) to give a brown oil. The brown oil was purified by reverse-phase flash chromatography in neutral mode on a Biotage Isolera Four (SNAP C18 60 g column with a gradient of 5% to 95% ACN through 10 CV) and the purest fraction was lyophilized to give 3-( 2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl] -2H-pyrrol-5-one 17 (570 mg, 1.35 mmol) was obtained as a white solid.
Yield: 55%

The mixture of enantiomers (105 mg) was separated by chiral SFC (AS 50 x 265-5 μm-300 g*EtOH 10%, 360 mL/min, 35 °C) to give 3-[2,2-difluorocyclopropyl]-1 -[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-2H-pyrrol-5-one (mirror image) Isomer 17-A, first elution, 27 mg, 0.066 mmol) and 3-[2,2-difluorocyclopropyl]-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[ 2,1-b][1,3,4]thiadiazol-5-yl]methyl]-2H-pyrrol-5-one (enantiomer 17-B, second elution, 27 mg, 0.066 mmol) was obtained. Ta.
Analytical chiral SFC (column AS, 3 mL/min, 30 °C, 20% MeOH, 100 bar): Enantiomer 17-A: 1.19 min, Enantiomer 17-B: 1.63 min

After separation, both enantiomers were repurified by reverse-phase flash chromatography Biotage Isolera Four in neutral mode (SNAP C18 12 g column with a gradient of 5% to 95% ACN in water through 10 CV) and directly lyophilized.

The following compounds were prepared following the same procedure.
3-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl] -2H-pyrrol-5-one 18 was prepared starting from XIII and III-B.
Yield: 50%

The mixture of enantiomers (110 mg) was separated by chiral SFC (AS 50x265-5μm-300g*MeOH 10%, 360mL/min, 35°C) to give 1-[[2-(methoxymethyl)-6- Methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[2,2-difluorocyclopropyl]-2H-pyrrol-5-one (enantiomer 18 -A, first elution, 15 mg, 0.042 mmol) and 1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl ]Methyl]-3-[2,2-difluorocyclopropyl]-2H-pyrrol-5-one (enantiomer 18-B, second elution, 19 mg, 0.053 mmol) was obtained.
Analytical chiral SFC (column AS, 3 mL/min, 30 °C, 20% MeOH, 100 bar): enantiomer 18-A: 1.04 min, enantiomer 18-B: 1.31 min

After separation, both enantiomers were purified by reverse-phase flash chromatography Biotage Isolera Four in neutral mode (SNAP C18 12 g column with a gradient of 5% to 95% ACN in water through 10 CV) and directly lyophilized. 3-(2,2-difluorocyclopropyl)-1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl] Methyl]-2H-pyrrol-5-one 19 was prepared starting from XXIII (as the free base) and III-B.
Yield: 11%

The mixture of enantiomers (138 mg) was separated by chiral SFC (AS 50×265-5 μm-300 g*EtOH 15%, 360 mL/min, 35°C) to give 1-[[6-(difluoromethyl)-2- (Methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-[2,2-difluorocyclopropyl]-2H-pyrrol-5-one (enantiomeric 19-A, first elution, 15 mg, 0.038 mmol) and 3-[2,2-difluorocyclopropyl]-1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2, 1-b][1,3,4]thiadiazol-5-yl]methyl]-2H-pyrrol-5-one (enantiomer 19-B, second elution, 19 mg, 0.048 mmol) was obtained.
Analytical chiral SFC (column AS, 3 mL/min, 30 °C, 20% EtOH, 100 bar): Enantiomer 19-A: 1.39 min, Enantiomer 19-B: 1.87 min

After separation, both enantiomers were purified by reverse-phase flash chromatography Biotage Isolera Four in neutral mode (SNAP C18 12 g column with a gradient of 5% to 95% ACN in water through 10 CV) and directly lyophilized.

3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]- 2H-pyrrol-5-one 20 was prepared following the same method starting from XIII and II-A.
Yield: 16%

1-[[2-(hydroxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro Synthesis of propyl-2H-pyrrol-5-one 21

1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro To a solution of a mixture of propyl)-2H-pyrrol-5-one 13 (1 eq., 100 mg, 0.26 mmol) in dichloromethane (1.5 mL) was added boron tribromide (5 eq., 1.3 mL, 1.3 mmol). It was added at room temperature and the mixture was stirred for 1 hour. Methanol was slowly added to the mixture (exothermic reaction) and the solvent was then evaporated to dryness to give a yellow oil. The yellow oil was purified by reverse phase flash chromatography Biotage Isolera Four (SNAP 30 g C18 with a gradient of 10% to 95% ACN in water) under neutral conditions. The purest fractions were combined and lyophilized to yield 1-[[2-(hydroxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl ]-3-(3,3,3-trifluoropropyl)-2H-pyrrol-5-one 21 (26 mg, 0.07 mmol) was obtained as a white solid.
Yield: 27%

1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- Trifluoropropyl)-2H-pyrrol-5-one 22 was prepared following the same method starting from 14.
Yield: 6%

1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- Trifluoroethyl)-2H-pyrrol-5-one 23 was prepared following the same method starting from 10.
Yield: 14%

Table (I) shows the IUPAC name (or name generated from Accelerys Draw 4.0 or Biovia Draw 16.1) of the compound, the ion peak observed in mass spectrometry, and the 1H NMR description.

In vitro and in vivo assays 1. Binding Assay for SV2A and SV2C Human SV2A and SV2C proteins were expressed in human embryonic kidney (HEK) cells. HEK SV2A and HEK SV2C membrane preparations were prepared as described in Gillard et al. (Eur. J. Pharmacol. 2006, 536, 102-108). To determine the affinity of unlabeled compounds, competition experiments were performed as follows: containing 2mM MgCl ₂ , 0.1% dimethyl sulfoxide and 10 increasing concentrations of unlabeled test compound (0.1 nM to 10 μM). [ ³ H]-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide (5 nM) and/or [ ³ H]-4R-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3, 4] Thiadiazol-5-yl]methyl}pyrrolidin-2-one (25 nM) membranes expressing SV2 protein (5-15 μg protein per assay) were incubated for 60 min at 37°C. At the end of the incubation period, membrane-bound radioligand was recovered by rapid filtration through GF/C glass fiber filters presoaked in 0.1% polyethyleneimine. The membrane was washed with at least four times the assay volume of ice-cold 50 mM Tris HCl buffer (pH 7.4). Filters were dried and radioactivity determined by liquid scintillation. The entire filtration process did not exceed 10 seconds. The measured affinity pIC ₅₀ values were corrected to pKi according to Cheng and Prusoff (Biochem. Pharmacol. 1973, 22(23), 3099-3108).

Compounds of formula (I) according to the invention typically exhibit pKi SV2A values of at least 6.5 and pKi SV2C values of at least 6.0.

Examples 18-B, 21, 22 and 23 exhibit pki SV2A values greater than 6.5 and less than or equal to 7.5. Examples 2, 5, 11, 18-A and 20 exhibit pki SV2A values greater than 7.5 and less than or equal to 8.0. Examples 1, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-A, 17-B, 19-A and 19-B are 8.0 or more Shows pki SV2A value less than 8.5

2. Seizure model Male NMRI mice (Charles River, Germany) weighing 22-32 g are used for all experiments. Animals are housed on a 12-hour/12-hour light/dark cycle with lights on at 6 a.m. and at a temperature maintained at 20-21° C. and approximately 40% humidity. Mice are housed in groups of 10 per cage (Type III). All animals have standard pelleted food and water available ad libitum before being randomly assigned to experimental groups of 10 mice each. All animal experiments will be conducted in accordance with national regulations on animal experiments and in accordance with the guidelines of Council of the European Communities Directive 2010/63/EU. The local ethics committee approved the experimental protocol.

6.1 6Hz Seizure Model The 6Hz model is performed according to a previously described protocol (Kaminski et al., Epilepsia (2004), 45, 864-867). Briefly, corneal stimulation (44 mA, 0.2 ms duration, monopolar square wave for 3 seconds at 6 Hz) is delivered by a constant current device (ECT Unit 57800; Ugo Basile, Comerio, Italy). 0.4% oxybuprocaine hydrochloride (Unicaine, Thea, France) is instilled into the eye before electrical stimulation. Mice are manually restrained during stimulation and released into observation cages (38 x 26 x 14 cm) immediately after electricity application. Seizures are often preceded by a brief period (approximately 2-3 seconds) of intense locomotor excitement (vigorous running and jumping). The animal then stands up and exhibits a "stunned" posture with automatic movements of the forelimbs and clonus, twitching of the sensory hairs, and tail raising. At the end of the seizure, the animal resumes normal exploratory behavior. The experimental endpoint is protection from seizures. Animals are considered protected if they resume normal exploratory behavior within 7 seconds of stimulation.

In vivo activity determined for test compounds typically falls between 0.05 mg/kg and 10 mg/kg after a single IP administration.

6.2 Pentylenetetrazole (PTZ) Seizure Model Pentylenetetrazol was administered at the previously established _CD97 dose of 89 mg/kg (a convulsive dose that induces clonic convulsions in all four limbs in 97% of mice). (Klitgaard et al., Eur. J. Pharmacol. (1998), 353, 191-206). Immediately after pentylenetetrazole injection, mice are placed individually in Perspex cages and observed for 60 minutes for the presence of clonic convulsions in all four limbs, and tonic hindlimb extension.

When tested, the in vivo activity determined for the accompanying example compounds typically falls between 0.5 mg/kg and 30 mg/kg after a single IP administration.

3. Azamulin Assay Cryopreserved human hepatocytes (pool of 20 donors, BSU batch from Celsis/IVT/Bioreclamation) were thawed according to the supplier's information. Viability (trypan blue exclusion) was over 75%. William's medium containing 2mM glutamine and 15mM Hepes in a 48-well plate at +37°C in an incubator (5% _CO2 ) for 30 minutes under gentle agitation (vibratory stirrer, Titramax 100, ~300rpm). Preincubation (250 μL of hepatocyte suspension at 2×10 ⁶ hepatocytes/mL) was performed using the following. After pre-incubation, add 250 μL of culture medium (see composition above) containing UCB compound (1 μM) or midazolam (positive control) in the presence or absence of azamulin (6 μM-specific CYP3A4/5 inhibitor). Incubation was started by adding to the hepatocytes. The final concentrations of UCB compound and azamulin in the culture are 0.5 μM and 3 μM, respectively. The cell suspension was rapidly rehomogenized by pipetting up and down twice. After 0, 30, 60, 120, 180 and 240 minutes of incubation, the reaction was carried out by transferring 50 μl of culture from a 96-well plate to the appropriate well containing 50 μL of ice-cold acetonitrile containing 1 μM ketoconazole as an internal standard. It stopped. Before each sampling, rehomogenize the cell culture by pipetting in and out twice.

After the end of the incubation, the 96-well plate is centrifuged at approximately 3700 rpm for 15 minutes at +4°C. Transfer 50 μL of supernatant to the well of another deep well plate to which 150 μL of H ₂ O Millipore was added. These samples were analyzed by micro UPLC/HR-MS for parent disappearance and monitoring of metabolite formation.

For each compound, the fraction metabolized by CYP3A4/5 (f _{m, CYP3A4} The contribution of CYP3A4/5, known as _/5 ), was calculated:

When tested, the fraction of the attached example compounds metabolized by CYP3A4/5 (f _{m , CYP3A4/5} ) typically comprises between 0 and 45%.

Examples 5, 9, 13 and 16 show the fraction metabolized by CYP3A4/5 (f _{m , CYP3A4/5} ) comprised between 0 and 10%. Examples 1, 3, 6, 7, 8, 10, 15 and 20 show a fraction (f _{m , CYP3A4/5} ) that is metabolized by CYP3A4/5 of greater than 10% and less than 20%. Examples 2, 3, 11, 12, 14, 17-A and 17-B show a fraction (f _{m , CYP3A4/5} ) metabolized by CYP3A4/5 of more than 20% and less than 45%.

Claims (14)

A compound according to formula (I) or a pharmaceutically acceptable salt thereof:

During the ceremony,
R ¹ is C _1-4 alkyl or C _3-5 cycloalkyl, any of these groups optionally substituted by one or more halogen substituents;
R ² is C _1-4 alkyl substituted with one hydroxy or alkoxy substituent;
R ³ is halogen; C _1-4 alkyl or C _3-4 cycloalkyl, and any of these groups is optionally substituted by one or more halogen atoms, formula (I) or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² is C _1-4 alkyl substituted with an alkoxy substituent. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-4 alkyl substituted with one or more halogen atoms. R ¹ is n-propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2-chloro-2,2-difluoroethyl, 2,2,2-trifluoroethyl or 2,2- 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is difluorocyclopropyl. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is 3,3,3-trifluoropropyl or 2,2-difluorocyclopropyl. ^2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydroxymethyl or methoxymethyl. ^2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is methoxymethyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ³ is a methyl group, a difluoromethyl group, a chlorine group, or a trifluoromethyl group. ^2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl or difluoromethyl. 1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole- 5-on;
1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2 -trifluoroethyl)-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3 -trifluoropropyl)-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one ;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoroethyl )-2H-pyrrol-5-one;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrol-5-one;
1-[[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoropropyl )-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-propyl-2H-pyrrole-5 -on;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2- trifluoroethyl)-2H-pyrrol-5-one ;
1 -[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2,2-trifluoro ethyl)-2H-pyrrol-5-one ;
1 -[[6-(1-fluorocyclopropyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2 ,2-trifluoroethyl)-2H-pyrrol-5-one;
3-(2-chloro-2,2-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole -5-yl]methyl]-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro propyl)-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- trifluoropropyl)-2H-pyrrol-5-one;
3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl] methyl]-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(2,2-difluoropropyl )-2H-pyrrol-5-one;
3R-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl ]Methyl]-2H-pyrrol-5-one;
3S-(2,2-difluorocyclopropyl)-1-[[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl ]Methyl]-2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3R-[2,2-difluorocyclopropyl] -2H-pyrrol-5-one;
1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3S-[2,2-difluorocyclopropyl] -2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3R-[2,2-difluorocyclo propyl]-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3S-[2,2-difluorocyclo propyl]-2H-pyrrol-5-one;
3-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]- 2H-pyrrol-5-one;
1-[[2-(hydroxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3-trifluoro propyl)-2H-pyrrol-5-one;
1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-3-(3,3,3- trifluoropropyl)-2H-pyrrol-5-one; and 1-[[6-(difluoromethyl)-2-(hydroxymethyl)imidazo[2,1-b][1,3,4]thiadiazole-5- 2. A compound according to claim 1 selected from the group consisting of yl]methyl]-3-(2,2,2-trifluoroethyl)-2H-pyrrol-5-one. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10. 12. A pharmaceutical composition according to claim 11 , comprising a pharmaceutically acceptable diluent or carrier. Pharmaceutical composition according to claim 11 or 12 for use in the treatment of epilepsy, epileptic seizures, seizure disorders, convulsions, especially intractable seizures. Compounds according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of epilepsy, epileptic seizures, seizure disorders, convulsions, in particular for the treatment of refractory seizures. , or the use of pharmaceutically acceptable salts thereof .